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Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2014.

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Glycogen Storage Disease Type I

Includes: Glycogen Storage Disease Type Ia, Glycogen Storage Disease Type Ib

, PhD, , MD, PhD, and , PhD, MS, CGC.

Author Information
, PhD
Division of Medical Genetics
Department of Pediatrics
Duke University Medical Center
Durham, North Carolina
, MD, PhD
Division of Medical Genetics
Department of Pediatrics
Duke University Medical Center
Durham, North Carolina
, PhD, MS, CGC
Division of Medical Genetics
Department of Pediatrics
Duke University Medical Center
Durham, North Carolina

Initial Posting: ; Last Update: September 19, 2013.

Summary

Disease characteristics. Glycogen storage disease type I (GSDI) is characterized by accumulation of glycogen and fat in the liver and kidneys, resulting in hepatomegaly and renomegaly. The two subtypes (GSDIa and GSDIb) are clinically indistinguishable. Although some untreated neonates present with severe hypoglycemia, more commonly, untreated infants present at age three to four months with hepatomegaly, lactic acidosis, hyperuricemia, hyperlipidemia, hypertriglyceridemia and/or hypoglycemic seizures. Affected children typically have doll-like faces with fat cheeks, relatively thin extremities, short stature, and protuberant abdomen. Xanthoma and diarrhea may be present. Impaired platelet function can lead to a bleeding tendency with frequent epistaxis. Untreated GSDIb is associated with impaired neutrophil and monocyte function as well as chronic neutropenia after the first few years of life, all of which result in recurrent bacterial infections and oral and intestinal mucosal ulcers. Long-term complications of untreated GSDI include growth retardation resulting in short stature, osteoporosis, delayed puberty, gout, renal disease, pulmonary hypertension, hepatic adenomas with potential for malignant transformation, polycystic ovaries, pancreatitis, and changes in brain function. Normal growth and puberty may be expected in treated children. Many affected individuals live into adulthood.

Diagnosis/testing. The diagnosis of GSDI is based on clinical presentation; abnormal blood/plasma concentrations of glucose, lactate, uric acid, triglycerides, and lipids; molecular genetic testing; and rarely abnormal enzymatic testing from a liver biopsy specimen. Biallelic mutations in G6PC (GSDIa) cause 80% of GSDI; biallelic mutations in SLC37A4 (GSDIb) cause 20% of GSDI.

Management. Treatment of manifestations: Medical nutritional therapy to maintain normal blood glucose concentrations, prevent hypoglycemia, and provide optimal nutrition for growth and development; allopurinol to prevent gout when dietary therapy fails to completely normalize blood uric acid concentration; lipid-lowering medications when lipid levels are elevated despite good metabolic control; citrate supplementation to help prevent development of urinary calculi or ameliorate nephrocalcinosis; angiotensin-converting enzyme (ACE) inhibitors to treat microalbuminuria; kidney transplantation for end-stage renal disease (ESRD); surgery or other interventions such as percutaneous ethanol injections and radiofrequency ablation for hepatic adenomas; liver transplantation for those individuals refractory to medical treatment or with hepatocellular carcinoma; and treatment with human granulocyte colony-stimulating factor (G-CSF) for recurrent infections for those with GSDIb.

Prevention of secondary complications: Improve hyperuricemia and hyperlipidemia and maintain normal renal function to prevent development of renal disease; maintain lipid levels within the normal range to prevent atherosclerosis and pancreatitis

Surveillance: Annual ultrasound examination of the kidneys after the first decade of life; liver ultrasound every 12 to 24 months until age 16 years; in individuals 16 years and older, liver CT or MRI with contrast every six to 12 months to monitor for hepatic adenomas; liver ultrasound or MRI examinations (depending on age) every three to six months if hepatic adenoma is detected; serum AST, ALT, and PT every six to 12 months; complete blood count every three months and periodic measurement of the spleen for those on G-CSF; systemic blood pressure at every clinic visit beginning in infancy; echocardiography every three years beginning at age ten years (or earlier if symptoms are present) to screen for pulmonary hypertension; routine monitoring of vitamin D levels.

Agents/circumstances to avoid: Diet should be low in fructose and sucrose; galactose and lactose intake should be limited to one serving per day; combined oral contraception should be avoided in women, particularly those with adenomas.

Evaluation of relatives at risk: Molecular genetic testing (if the family-specific mutations are known) and/or evaluation by a metabolic physician soon after birth (if the family-specific mutations are not known) allows for early diagnosis and treatment of sibs at risk for GSDI.

Genetic counseling. GSDI is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Heterozygotes (carriers) are asymptomatic. Carrier testing for at-risk family members and prenatal diagnosis for pregnancies at increased risk are possible if both disease-causing mutant alleles of an affected family member have been identified.

Diagnosis

The two major subtypes of glycogen storage disease type I (GSDI) [Chen 2001, Matern et al 2002, Chen 2004, Chen & Bali 2004] are:

  • GSD type Ia, caused by the deficiency of glucose-6-phosphatase (G6Pase) catalytic activity
  • GSD type Ib, caused by a defect in glucose-6-phosphate translocase (transporter)

The lack of either G6Pase catalytic activity or glucose-6-phosphate translocase (transporter) activity in the liver leads to inadequate conversion of glucose-6-phosphate into glucose through normal glycogenolysis and gluconeogenesis pathways, resulting in severe hypoglycemia and many other signs and symptoms of the GSDI disorders.

The diagnosis of GSDI is suspected in individuals with the following [Chen 2001, Rake et al 2002a, Rake et al 2002b, Chen 2004, Chen & Bali 2004]:

  • Clinical findings including signs of hypoglycemia, hepatomegaly, and growth failure
  • Abnormal laboratory findings including:
    • Hypoglycemia. Fasting blood glucose concentration lower than 60 mg/dL (reference range: 70-120 mg/dL);
    • Lactic acidosis. Blood lactate higher than 2.5 mmol/L (reference range: 0.5-2.2 mmol/L);
    • Hyperuricemia. Blood uric acid higher than 5.0 mg/dL (reference range: 2.0-5.0 mg/dL);
    • Hyperlipidemia
      • Triglycerides higher than 250 mg/dL (reference range: 150-200 mg/dL); Hypertriglyceridemia causes the plasma to appear "milky."
      • Cholesterol higher than 200 mg/dL (reference range: 100-200 mg/dL).

Such suspicions can be further strengthened by:

  • Glucagon or epinephrine challenge test. Administration of glucagon or epinephrine causes little or no increase in blood glucose concentration, but both increase serum lactate concentrations significantly.
  • Liver histology. Histopathologic liver findings in GSD I include distention of the liver cells by glycogen and fat; PAS positive and diastase sensitive glycogen that is uniformly distributed within the cytoplasm; normal or only modestly increased glycogen; and large and numerous lipid vacuoles. Fibrosis and cirrhosis do not occur in GSDI.

    Note: As liver biopsy is invasive, it should only be done when a diagnosis cannot be made using blood-based assays, such as mutation analysis (see following). Liver tissue may be obtained at the same time as another surgery (e.g., G-tube placement).

The diagnosis of GSDI is confirmed by identification of EITHER:

OR

  • Deficient hepatic enzyme activity. A sample of 15-20 mg of snap-frozen liver obtained by percutaneous or open biopsy should be shipped on dry ice via overnight delivery to the clinical diagnostic laboratory:
    • Glucose-6-phosphatase (G6Pase) catalytic activity. The normal G6Pase enzyme activity level in liver is 3.50±0.8 µmol/min/g tissue:
      • In most individuals with GSDIa, the G6Pase enzyme activity is lower than 10% of normal.
      • In rare individuals with milder clinical manifestations, the G6Pase enzyme activity can be higher (>1.0 µmol/min/g tissue and < 2.0 µmol/min/g tissue).
  • Glucose-6-phosphate translocase (transporter) activity. G6P translocase activity using an in vitro assay is difficult to measure in frozen liver; therefore, fresh (unfrozen) liver is often needed to assay enzyme activity accurately. As a result, most clinical diagnostic laboratories refrain from offering this enzyme activity assay.

Note: Because of its relatively high sensitivity, molecular genetic testing is increasingly the preferred confirmatory test when weighed against the need for liver biopsy to determine the level of enzyme activity (see preceding). However liver biopsy can additionally be used to obtain histology and electronic micrographic information

Table 1. Summary of Molecular Genetic Testing Used in Glycogen Storage Disease Type I

Gene 1 Proportion of GSDI Attributed to Mutations in This GeneTest Method Mutations Detected 2Mutation Detection Frequency by Gene, Test Method, and Population Group 3
Ashkenazi JewishNon-Ashkenazi Jewish
G6PC80%Targeted mutation analysisp.Arg83Cys 493% 5 - 100% 6~30% 7
p.Gln347* 40% 615%
Sequence analysisSequence variants 894% 5, 7
Deletion / duplication analysis 9Exonic or whole-gene deletionsUnknown 10
SLC37A420%Sequence analysisSequence variants 8 95%
Deletion / duplication analysis 9Exonic or whole-gene deletionsUnknown 10

1. See Table A. Genes and Databases for chromosome locus and protein name.

2. See Molecular Genetics for information on allelic variants.

3. The ability of the test method used to detect a mutation that is present in the indicated gene

4. Mutations in panel may vary by laboratory.

5. Rake et al [2000]

6. Both mutations could not be detected in some individuals with clinically and enzymatically confirmed GSDIa [Ekstein et al 2004]

7. Seydewitz & Matern [2000] (in 40 affected individuals)

8. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here

9. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

10. Although the frequency of (multi)exonic deletions is unknown, very few have been reported in either of these genes [Janecke et al 2000; clinical laboratory observation, unpublished].

Clinical Description

Natural History

The clinical manifestations of GSDI are growth retardation leading to short stature and accumulation of glycogen and fat in the liver and kidneys, which result in hepatomegaly and renomegaly, respectively [Chen 2001, Chou et al 2002, Chen & Bali 2004].

Although some neonates present with severe hypoglycemia, more commonly untreated infants present at age three to four months with hepatomegaly, lactic acidosis, hyperuricemia, hyperlipidemia, hypertriglyceridemia and/or hypoglycemic seizures. Hypoglycemia and lactic acidosis can develop after a short fast (2-4 hours).

Untreated children typically have doll-like faces with fat cheeks, relatively thin extremities, short stature, and protuberant abdomen caused by massive hepatomegaly. The spleen is of normal size. Xanthoma and diarrhea may be present. Impaired platelet function can lead to a bleeding tendency, making epistaxis a frequent problem.

In addition to the above findings, untreated GSDIb is associated with chronic neutropenia and impaired neutrophil and monocyte function. Neutropenia is noted typically after the first few years of life, resulting in recurrent bacterial infections and oral and intestinal mucosal ulcers [Visser et al 1998, Visser et al 2002a]. Oral manifestations such as ulcers, gingivitis, periodontal disease, bleeding diathesis, dental caries, and delayed dental maturation and eruption have been reported in a few affected individuals [Mortellaro et al 2005].

Long-term complications of untreated GSDI include the following [Weinstein et al 2001, Rake et al 2002a]:

  • Short stature. Children with GSDI have poor growth and short stature in adulthood; however, with strict dietary regimens and control, growth and final adult stature have improved [Weinstein & Wolfsdorf 2002, Mundy et al 2003].
  • Osteoporosis. Frequent fractures and radiographic evidence of osteopenia are common. Bone mineral content can be significantly reduced even in prepubertal children [Schwahn et al 2002, Visser et al 2002b, Wolfsdorf 2002, Rake et al 2003, Cabrera-Abreu et al 2004].
  • Delayed puberty. Untreated affected individuals historically showed delayed onset of puberty; however, with adherence to a strict dietary regimen, age of onset of puberty can be normal [Sechi et al 2013].
  • Gout. Although hyperuricemia is present in young affected children, gout rarely develops in untreated children before puberty [Matern et al 2002].
  • Renal disease. Proteinuria, hypertension, renal stones, nephrocalcinosis, and altered creatinine clearance may occur in younger affected individuals. With disease progression, interstitial fibrosis becomes evident. Some individuals progress to end-stage renal disease (ESRD) and may require a renal transplant [Simoes et al 2001, Weinstein & Wolfsdorf 2002, Iida et al 2003].
  • Systemic hypertension. Systemic hypertension does not usually develop until the second decade or later and is often found in those individuals with GSDI who also have renal disease [Rake et al 2002a].
  • Pulmonary hypertension. Overt pulmonary hypertension as a long-term complication of GSDI has been reported [Kishnani et al 1996, Humbert et al 2002]. Those at highest risk typically have a coexisting condition that also predisposes them to developing pulmonary hypertension [Pizzo 1980, Furukawa et al 1990, Hamaoka et al 1990, Bolz et al 1996].
  • Hepatic adenomas with potential for malignant transformation. By the second or third decade of life, most affected individuals exhibit hepatic adenomas, a complication of which is intrahepatic hemorrhage. In some, the adenomas may undergo malignant transformation into hepatocellular carcinoma (HCC) [Kelly & Poon 2001, Kudo 2001, Weinstein & Wolfsdorf 2002, Franco et al 2005]. Evidence for a relationship between poor metabolic control and the development of adenomas is conflicting [Di Rocco et al 2007, Wang et al 2011]. While it has been reported, the pathogenesis is likely to be multifactorial [Wang et al 2011].
  • Pancreatitis. Pancreatitis, a secondary complication of hypertriglyceridemia, is seen in some affected individuals, particularly those in poor dietary compliance.
  • Neurocognitive effects. Changes in IQ, MRI findings, and EEG were found to correlate with the frequency of hypoglycemic episodes, particularly in those in poor dietary compliance [Melis et al 2004].
  • Anemia. Anemia is a common problem in individuals with GSDI [Rake et al 2002a], although the pathophysiology seems to be different in individuals with GSDIa versus individuals with GSDIb [Wang et al 2012]. Those with GSDIa and severe anemia are likely to have hepatic adenomas, while those with GSDIb and severe anemia may have enterocolitis [Wang et al 2012].
  • Vitamin D deficiency. In one study, 16/26 affected individuals had suboptimal levels of vitamin D suggesting that 25(OH)-vitamin D levels should be measured on a routine basis [Banugaria et al 2010].
  • Polycystic ovaries. Virtually all affected females have ultrasound findings consistent with polycystic ovaries. While this may affect ovulation and fertility in some females, in general fertility does not seem to be reduced [Lee et al 1995, Martens et al 2008, Sechi et al 2013].
  • Irregular menstrual cycles. About half of women with GSDI were found to have irregular menstrual cycles [Sechi et al 2013].
  • Menorrhagia. Menorrhagia appears to be a problem for reproductive-age females with GSDI [Author, manuscript submitted]. This issue should be addressed when reviewing the clinical history of reproductive-age females with GSDI. Referral to a gynecologist for management should be made when appropriate.

In addition, individuals with GSDIb may develop:

  • Neutropenia and impaired neutrophil function. Neutropenia and recurrent infections are common in individuals with GSDIb and can also occur in a small subset of individuals with GSDIa [Weston et al 2000]. Evidence suggests that the neutropenia in those with GSDIb may be caused by increased apoptosis and migration of the neutrophils to inflamed tissues rather than by impairment in maturation [Visser et al 2012].
  • Inflammatory bowel disease/enterocolitis is common in individuals with GSDIb [Visser et al 2002b].
  • Thyroid autoimmunity. The prevalence of thyroid autoimmunity and hypothyroidism has been found to be increased in individuals with GSDIb [Melis et al 2007].

In the past, many individuals with GSDI who were untreated died at a young age and the prognosis was guarded in survivors. However, early diagnosis and treatment have improved prognosis. Normal growth and puberty may be expected in treated children, and many affected individuals live into adulthood. However, it is not known if all long-term secondary complications can be avoided by good metabolic control. Some individuals treated early develop hepatic adenoma and proteinuria in adulthood.

Genotype-Phenotype Correlations

No strong genotype-phenotype correlations have been identified for GSDI.

G6PC. A few studies have suggested that individuals with GSDIa who are homozygous for the c.648G>T splicing mutation are at increased risk of developing hepatocellular carcinoma (HCC) [Nakamura et al 1999].

Individuals with GSDIa who are homozygous for the mutation p.Gly188Arg were reported to have a GSDIb-like phenotype with neutropenia [Weston et al 2000].

SLC37A4. No clear phenotype-genotype correlations have been found in GSDIb.

Nomenclature

G6Pase is a multi-component enzyme complex often referred to as the G6Pase system. Some authors preferred to classify GSD type I into 'type Ia' and 'type I non-a' phenotypes because most individuals previously classified as having GSDIc and Id have now been shown to have mutations in SLC37A4 [Veiga-da-Cunha et al 1998, Veiga-da-Cunha et al 1999, Veiga-da-Cunha et al 2000]. However, all newer publications prefer to classify the GSDI subtypes as GSD Ia and GSD Ib. Hence, the classification of GSDI into four subtypes no longer exists.

Historically, GSD-I is also referred to as Von Gierke disease after Dr. Von Gierke, who first described the disease in 1929.

Prevalence

Overall incidence of GSDI is one in 100,000.

GSDIa is the most common GSD subtype in individuals of European descent.

In Ashkenazi Jews, it is estimated that the carrier frequency of the most common mutation (p.Arg83Cys) is 1.4% and disease prevalence is one in 20,000.

The increased frequency of some mutations in different ethnic groups, such as c.648G>T in 88% of Japanese and p.Tyr128Thrfs*3 (c.378_379dupTA) in 50% of American Hispanics, may reflect population-specific differences in disease prevalence [Janecke et al 2001, Chou et al 2002, Ekstein et al 2004].

Differential Diagnosis

GSD type III (debranching enzyme deficiency) is clinically similar to GSD type I (GSDI) in infancy. However, with age, the clinical findings and biochemical work up can differentiate between the two disorders. Major manifestations of GSDIII include the following:

  • Hypoglycemia that improves with age
  • Hepatomegaly caused by abnormal glycogen accumulation
  • Hyperlipidemia
  • Skeletal myopathy and increased serum creatine kinase (CK) concentration (in GSDIIIa only)

In contrast to GSDI, GSDIII is characterized by the following:

  • Normal glucagon response two hours after a carbohydrate meal
  • Elevated liver transaminases
  • Myopathy/cardiomyopathy (GSD-IIIa only)
  • Absence of renomegaly

Other conditions that can present clinically like GSDI include GSD type VI, GSD type IX, fructose-1,6-bisphosphatase deficiency, diabetes mellitus, and Niemann-Pick type B (see Acid Sphingomyelinase Deficiency).

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with glycogen storage disease type I (GSDI), the following evaluations are recommended:

  • Serum/plasma concentration of glucose, lactic acid, uric acid, 25(OH)-vitamin D, and lipids including cholesterol and triglycerides
  • Complete blood count to evaluate for neutropenia in individuals with GSDIb and those with GSDIa due to homozygosity for the p.Gly188Arg mutation in G6PC
  • Measurement of length or height and weight and calculation of body mass index
  • Evaluation of nutritional status
  • Liver imaging to evaluate for hepatomegaly
  • Liver function tests
  • Kidney imaging to evaluate for renomegaly
  • Kidney function tests
  • Bleeding time to evaluate platelet function
  • Measurement of bone density (after the first decade)
  • Screening to detect systemic and pulmonary hypertension
  • Medical genetics and metabolic specialist consultation

Treatment of Manifestations

Treatment includes care by a metabolic team familiar with the medical issues associated with long-term management of persons with GSD. At a minimum, such a team should include the following:

  • Metabolic specialist familiar with the multisystem nature of GSDI. This individual should monitor current medical issues while providing anticipatory guidance and feedback regarding potential future medical issues (e.g., malignant transformation of liver adenomas, kidney stone management).
  • Metabolic nutritionist who monitors nutritional adequacy, weight management, food choices, and timing of cornstarch and food intake, and who works with the individual and/or family to assure understanding of the parameters of compliance at different life stages.
  • Health care provider (nurse, genetic counselor, physician assistant) familiar with the inheritance of GSDI who can address questions related to implications of this diagnosis for other family members and future childbearing of the affected person. Such an individual may focus on health care compliance by assisting affected children to transition to independent understanding and management of their GSDI-related health care issues.

Care teams often establish relationships with additional health care workers including:

  • Medical social worker to assist with formula acquisition and access to community-based services (e.g., access to regular exercise and physical activity plans) and provide early intervention for long-term health management and wellness;
  • Psychologist with experience in helping affected individuals cope with eating disorders and chronic illness.

Medical Nutrition Therapy Goals

Maintain normal glucose levels and prevent hypoglycemia:

  • Frequent daytime feedings. Small frequent meals and snacks high in complex carbohydrates with additional feedings between meals and before bedtime are recommended (monitoring of blood glucose concentration may help adjust feeding schedules to meet individual needs).
  • Nighttime intragastric continuous glucose infusion through a nasogastric tube or a gastrostomy tube. An optimal infusion should provide 8-10 mg/kg/min glucose in an infant and 6-8 mg/kg/min glucose in an older child.
  • Uncooked cornstarch orally can be started during infancy [Wolfsdorf & Crigler 1999, Weinstein & Wolfsdorf 2002]. Cornstarch should be given between meals or before bedtime so as not to interfere with appetite at meal time.
    • There is no consensus on the age at which cornstarch therapy should be initiated but it is often introduced around one year of age.
    • The severity and recurrence of hypoglycemic episodes determines the timing of corn starch therapy initiation via nasogastric tube or gastrostomy tube in infancy and childhood and oral ingestion in teenagers and adults.
    • Note: Recommendations for cornstarch dosing are: 1.6 g/kg body weight every four hours for infants, 1.7-2.5 g/kg body weight every six hours for young children through puberty, and 1.7-2.5 g/kg body weight given before bed time for adults.

Provide optimal nutrition for growth and development:

  • Complex carbohydrates (60%-70% of recommended total energy intake) including cornstarch and starches from whole-grain bread, rice, and potatoes for children and adolescents and rice cereals for infants

    Note: (1) Intake of sucrose and fructose should be restricted for infants and older children [Rake et al 2002a, Rake et al 2002b]. Avoid sugar, fruits, fruit juice, high-fructose corn syrup, sorbitol, cane juice, and other foods that cannot be broken down into glucose. (2) Intake of lactose and galactose should be limited [Rake et al 2002a, Rake et al 2002b]. One serving per day for an older child usually entails 1.5 ounces cheese OR 1 cup of yogurt OR 1 cup of skim milk. (3) Blood glucose monitoring for hypoglycemia is important so that overtreatment with cornstarch may be avoided. If excess weight gain occurs, consider decreasing the amount of cornstarch gradually over time and mixing cornstarch in water instead of Prosobee® or Tolerex®.
  • Protein (10%-15% of recommended total energy intake) of high quality, high biologic value (e.g., protein low in fat). Soy formula (Prosobee®) and soy milk (lactose/galactose free) can be used both in infancy and childhood for carbohydrate and protein needs.
    Note: (1) Avoid soy milks that are sweetened with sucrose; the ones with rice syrup or brown rice syrup can be taken. (2) Soy milk mixed with cane sugar should be avoided.
  • Fat (10%-15% of recommended total energy intake) as part of a low-fat diet that includes heart-healthy fats such as canola oil and olive oil. Note: Families need explicit guidelines on fat intake as part of monitoring total energy intake and avoiding excessive weight gain.
  • Calcium and vitamin D supplements to support bone growth and mineralization. If the individual is not on calcium-fortified soy milk, calcium citrate or calcium carbonate with vitamin D is recommended to meet RDA for age needs and to prevent nutritional deficiencies.
  • Iron supplements in complete multivitamins with minerals (100% RDA iron and zinc) to avoid anemia and iron deficiency

Treatment of Other Manifestations

Allopurinol, a xanthine oxidase inhibitor, is used to prevent gout when dietary therapy fails to completely normalize blood uric acid concentration, especially after puberty.

Lipid-lowering medications, such as HMG-CoA reductase inhibitors and fibrate (e.g., Lipitor®, gemfibrozil), are used when lipid levels remain elevated despite good metabolic control, especially after puberty.

Citrate supplementation may help prevent or ameliorate nephrocalcinosis and the development of urinary calculi [Weinstein et al 2001, Wolfsdorf & Weinstein 2003].

  • In young children, an initial dose of 1 mEq/kg/day in liquid form divided into three doses should be instituted. The dose should be increased based on urinary citrate excretion.
  • In older children and adults, potassium citrate tablets can be started at a dose of 10 mEq three times a day. Citrate use should be monitored as it can cause hypertension and life-threatening hyperkalemia in affected individuals with renal impairment. Sodium levels should also be monitored.

Angiotensin-converting enzyme (ACE) inhibitors such as captopril are used to treat microalbuminuria, an early indicator of renal dysfunction.

Kidney transplantation can be performed for ESRD [Weinstein et al 2001].

Hepatic adenomas can be treated with surgery or other interventions including percutaneous ethanol injections and radiofrequency ablation [Yoshikawa et al 2001].

Liver transplantation can be considered when other interventions have failed [Faivre et al 1999].

Human granulocyte colony-stimulating factor (G-CSF) can be used to treat recurrent infections:

  • G-CSF may increase the number and improve the function of circulating neutrophils.
  • G-CSF may improve the symptoms of Crohn's-like inflammatory bowel disease in individuals with GSDIb [Myrup et al 1998, Visser et al 2000, Calderwood et al 2001, Steinmetz et al 2001, Visser et al 2002c].
  • G-CSF should be administered subcutaneously starting at 1.0 μg/kg given daily or every other day. The G-CSF dose should be increased stepwise at approximately two-week intervals until the target absolute neutrophil count (ANC) of greater than 500 to up to 1.0 x 109/L is reached.

Prevention of Primary Manifestations

See Treatment of Manifestations.

Prevention of Secondary Complications

Improve hyperuricemia and hyperlipidemia and maintain normal renal function to prevent the development of renal disease.

Maintain lipid levels within the normal range to prevent atherosclerosis and pancreatitis

Surveillance

Annual ultrasound examination of the kidneys for nephrocalcinosis should be initiated after the first decade of life.

Surveillance of the liver may include the following:

  • In younger children (up to 16 years), liver ultrasounds should be performed at diagnosis and thereafter every 12 to 24 months. In affected individuals who are 16 years and older, liver computed tomography (CT) or magnetic resonance imaging (MRI) scanning using intravenous contrast should be done every 6-12 months to monitor for hepatic adenoma formation [Franco et al 2005]
  • Serum AST, ALT, and PT should be evaluated every 6-12 months to monitor for liver damage.
  • When hepatic adenoma is detected, ultrasound examination of the liver every three to six months (or more frequently as indicated) is appropriate. Liver imaging studies (MRI/CT scan) for liver size, adenomas, evidence of portal hypertension, or liver carcinoma (nodules, heterogeneous echogenic shadows) should be considered [Faivre et al 1999, Franco et al 2005].
    • Serum AFP and CEA levels are not reliable markers of hepatocellular carcinoma [Shieh et al 2012].

For those individuals treated with G-CSF, serial blood counts should be performed approximately every 3 months to assess response to treatment and, although the risk of acute myeloid leukemia (AML) is low, to evaluate for the presence of myeloblasts in the blood. Any imaging performed for liver surveillance, such as ultrasound, computed tomography, or magnetic resonance imaging, should include measurements of the spleen to identify and monitor splenomegaly.

Cardiovascular surveillance

  • Systemic blood pressure measurements should be obtained at all clinic visits beginning in infancy.
  • Screening for pulmonary hypertension by echocardiography every three years beginning at age ten years (or earlier if symptoms are present) is appropriate.

25(OH)-vitamin D levels should be monitored routinely and treated as needed.

Agents/Circumstances to Avoid

Diet should be low in fructose and sucrose.

Limit galactose and lactose intake to one serving per day.

Due to potential negative effects of sex hormones on hepatic adenomas, combined oral contraception must be avoided in women with GSDI, especially those with adenomas [Sechi et al 2013].

Evaluation of Relatives at Risk

If the family-specific mutations are known, molecular genetic testing of sibs at risk for GSD type I allows for early diagnosis and treatment with much-improved outcome.

If the family-specific mutations are not known or if molecular genetic testing is not available, sibs at risk for GSDI should be evaluated by a metabolic physician soon after birth for symptoms pertaining to GSDI.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

Although successful pregnancies have been reported in women with GSDI, certain precautions should be taken:

  • Pre-pregnancy counseling regarding diet to avoid low blood glucose and to stress the importance of blood glucose monitoring prior to and during pregnancy
  • Baseline ultrasound of liver and kidneys prior to pregnancy
  • Consideration of referral to high-risk obstetrician
  • Review of medications prior to conception to weigh risks and benefits:
    • Exposure to ACE inhibitors in the second and third trimesters of pregnancy can cause fetal damage and death.
    • No data on the use of allopurinol during pregnancy in humans exist; however, high doses have been shown to interfere with embryo development in animal models.
    • Lipid-lowering drugs may also lead to adverse fetal effects and should be avoided during pregnancy.

Metabolic control should be followed closely throughout the pregnancy. Because carbohydrate requirements may increase with pregnancy, glucose levels should be monitored closely and treated accordingly [Martens et al 2008, Dagli et al 2010, Yamamoto et al 2010].

Abdominal ultrasound should be performed every six to 12 weeks. Sechi et al [2013] reported an increase in the size of pre-existent adenomas and the development of new adenomas during pregnancy and recommended monitoring by imaging before, during, and after pregnancy. Resection of large (≥5cm) or growing adenomas before pregnancy has been recommended [Terkivatan et al 2000].

Renal function should be followed closely, as this may worsen during pregnancy [Martens et al 2008, Dagli et al 2010, Yamamoto et al 2010]. Development of renal calculi has been reported in pregnant women with GSDIb [Dagli et al 2010].

Glucose infusion during labor has been used [Martens et al 2008, Dagli et al 2010].

Platelet count, hemoglobin, and clotting studies should be performed due to the potential for increased bleeding at delivery [Lewis et al 2005].

Therapies Under Investigation

A new physically modified cornstarch is under clinical investigation [Bhattacharya et al 2007].

Gene therapy is in early stages of research in animals [Yiu et al 2007, Koeberl et al 2008, Chou & Mansfield 2011].

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Glycogen storage disease type I (GSDI) is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

  • The parents of an affected child are obligate heterozygotes (i.e., carriers of one mutant allele).
  • Heterozygotes (carriers) are asymptomatic.

Sibs of a proband

  • At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
  • Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.
  • Heterozygotes (carriers) are asymptomatic.

Offspring of a proband. The offspring of an individual with GSDI are obligate heterozygotes (carriers) for a disease-causing mutation.

Other family members of a proband. Each sib of the proband's parents is at a 50% risk of being a carrier.

Carrier Detection

Molecular genetic testing. Carrier testing is possible if the family-specific mutations are known.

Biochemical genetic testing. Enzymatic testing is unreliable and not available for use in carrier detection.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on testing at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

  • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

Molecular genetic testing. If the disease-causing mutations have been identified in a family member, prenatal testing for pregnancies at increased risk is possible either through a clinical laboratory or a laboratory offering custom prenatal testing.

Biochemical testing. Prenatal testing based on assay of G6Pase enzymatic activity or G6Ptranslocase enzymatic activity is not available because of the low accuracy rate and risk associated with fetal liver biopsy. The G6Pase enzyme assay in vitro may not differentiate a carrier from either a normal or an affected pregnancy [Chen et al 2002] and thus is not recommended.

Requests for prenatal testing for conditions which (like GSDI) do not affect intellect and have some treatment available are not common. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although most centers would consider decisions about prenatal testing to be the choice of the parents, discussion of these issues with genetic counselors or a geneticist is appropriate.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutations have been identified.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • Association for Glycogen Storage Disease (AGSD)
    PO Box 896
    Durant IA 52747
    Phone: 563-514-4022
    Email: maryc@agsdus.org
  • Children Living with Inherited Metabolic Diseases (CLIMB)
    Climb Building
    176 Nantwich Road
    Crewe CW2 6BG
    United Kingdom
    Phone: 0800-652-3181 (toll free); 0845-241-2172
    Fax: 0845-241-2174
    Email: info.svcs@climb.org.uk

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A. Glycogen Storage Disease Type I: Genes and Databases

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B. OMIM Entries for Glycogen Storage Disease Type I (View All in OMIM)

232200GLYCOGEN STORAGE DISEASE Ia; GSD1A
232220GLYCOGEN STORAGE DISEASE Ib; GSD1B
602671SOLUTE CARRIER FAMILY 37 (GLUCOSE-6-PHOSPHATE TRANSPORTER), MEMBER 4; SLC37A4
613742GLUCOSE-6-PHOSPHATASE, CATALYTIC; G6PC

G6PC

Normal allelic variants. G6PC spans approximately 12.5 kb and consists of five coding exons.

Pathologic allelic variants. At present, 86 disease-causing mutations, which are scattered throughout the gene, have been reported (see Table A) and some additional as-yet unreported mutations identified through clinical testing of known affected individuals. These mutations include: nucleotide changes resulting in missense and nonsense mutations, small deletions and insertions involving frameshift and splicing, and other rare gene rearrangements. See Table 2.

The following are some ethnic-specific common mutations that account for approximately 90% of known disease alleles [Veiga-da-Cunha et al 1998, Chou et al 2002, Matern et al 2002, Chou & Mansfield 2008].

Table 2. G6PC Pathologic Allelic Variants Discussed in This GeneReview

DNA Nucleotide Change
(Alias 1)
Protein Amino Acid ChangeReference Sequences
c.79delC
(158delC)
p.Gln27Argfs*9NM_000151​.2
NP_000142​.1
c.247C>Tp.Arg83Cys
c.248G>Ap.Arg83His
c.378_379dupTA (459insTA)p.Tyr128Thrfs*3
c.562G>C
(641G>C)
p.Gly188Arg
c.809G>Tp.Gly270Val
c.648G>T
(G727T)
Silent amino acid change (Leu216Leu) that creates new splice site resulting in premature termination at p.Tyr202* 2
c.724C>Tp.Gln242*
c.979_981delp.Phe327del
c.1039C>T
(1118C>T)
p.Gln347*
c.379_380dupTA
(459insTA)
p.Tyr128Thrfs*3

Note on variant classification: Variants listed in the table have been provided by the author(s). GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1. Variant designation that does not conform to current naming conventions

2. Lam et al [1998]

Normal gene product. G6Pase is a multi-component enzyme system localized in the endoplasmic reticulum membrane. It helps catalyze the terminal reaction of both glucogenolysis and gluconeogenesis, hydrolyzing G6P to glucose and inorganic phosphate in hepatocytes and renal cells.

Abnormal gene product. The disease-causing mutations in the G6Pase system cause deficiency of the catalytic activity of the enzyme, thus preventing release of free glucose in the affected tissues (liver, kidney, intestinal mucosa).

SLC37A4

Normal allelic variants. SLC37A4 spans approximately 5.3 kb and comprises nine exons [Veiga-da-Cunha et al 1998, Veiga-da-Cunha et al 2000, Chou et al 2002, Matern et al 2002].

Pathologic allelic variants. At present, 82 disease-causing mutations are known (see Table A), and some additional as-yet unreported mutations identified through clinical testing of known affected individuals. Most of them are nucleotide substitutions resulting in missense or nonsense mutations. Some small deletions and splicing mutations and one large deletion have also been found. See Table 3.

Some ethnic-specific common mutations:

Table 3. SLC37A4 Pathologic Allelic Variants Discussed in This GeneReview

DNA Nucleotide Change
(Alias 1)
Protein Amino Acid ChangeReference Sequences
c.352T>C
(521T>C)
p.Trp118ArgNM_001467​.4
NP_001458​.1
c.1015G>T
(1184G>T)
p.Gly339Cys
c.1042_1043delCT
(1211delCT)
p.Leu348Valfs*53
c.1099G>Ap.Ala367Thr

Note on variant classification: Variants listed in the table have been provided by the author(s). GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1. Variant designation that does not conform to current naming conventions

Normal gene product. Glucose-6-phosphate translocase (transporter) produces a transport protein that helps transport G6P into the lumen of the endoplasmic reticulum from the cytoplasm and endoplasmic reticulum membrane compartment. G6P transporter is expressed ubiquitously in tissues like liver, kidney, large intestine, small intestine, skeletal muscle, and to a lesser extent, the brain and heart, unlike G6Pase.

Abnormal gene product. Deficiency of G6P transporter prevents G6P from crossing the microsomal membrane for hydrolysis and production of glucose.

References

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Chapter Notes

Acknowledgments

We acknowledge the AGSD association, patients with GSD, physicians treating patients with GSD, and laboratory personnel for their untiring work and cooperation.

Revision History

  • 19 September 2013 (me) Comprehensive update posted live
  • 23 December 2010 (me) Comprehensive update posted live
  • 2 September 2008 (me) Comprehensive update posted live
  • 19 April 2006 (me) Review posted to live Web site
  • 30 March 2005 (ytc) Original submission
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